Chapter VII
The Nature Of Infection.—The Invasion Of The Body From Its Surfaces.—The Protection Of These Surfaces.—Can Bacteria Pass Through An Uninjured Surface.—Infection From Wounds.—The Wounds In Modern Warfare Less Prone To Infection.—The Relation Of Tetanus To Wounds Caused By The Toy Pistol.—The Primary Focus Or Atrium Of Infection.—The Dissemination Of Bacteria In The Body.—The Different Degrees Of Resistance To Bacteria Shown By The Various Organs.—Mode Of Action Of Bacteria.—Toxin Production.—The Resistance Of The Body To Bacteria.—Conflict Between Parasite And Host.—On Both Sides Means Of Offense And Defense.—Phagocytosis.—The Destruction Of Bacteria By The Blood.—The Toxic Bacterial Diseases.—Toxin And Antitoxin.—Immunity.—The Theory Of Ehrlich.
As has been said, infection consists in the injury of the body by living organisms which enter it. The body is in relation to the external world by its surfaces only, and organisms must enter it by some one of these surfaces. It is true that the bacteria in the intestine—either those normally present or unusual varieties—may, under certain circumstances, produce substances which are injurious when absorbed; but this is not infection, and is analogous to any other sort of poisoning. Each surface of the body has its own bacterial flora. Organisms live on the surface either on matter which is secreted by the surface or they use up an inappreciable amount of body material. Many of these bacteria are harmless, some are protective, producing by their growth such changes in the surface fluids that these become hostile to the existence of other and pathogenic forms. The surfaces also frequently harbor pathogenic organisms which await some condition to arise which will permit them to effect entrance into the tissues.
The surfaces of the body protect from invasion to a greater or less degree. The skin protects by the impervious horny layer on the outside, the external cells of which are dead and constantly being thrown off. Bacteria are always found on and in this layer, but the conditions for growth here are not very favorable and the surface is constantly cleansed by desquamation. The new cells to supply the loss are produced in the deepest layer of the epidermis, and the movement of cells and fluids takes place from within outwards. The protection is less perfect about the hairs and the sweat glands. Infection by the route of the sweat glands is, however, uncommon, for the sweat is a fluid unfavorable for bacterial growth and the flow acts mechanically in washing away organisms which may have entered the ducts. Infection by the route of the hair follicles is common. There is no mechanical cleansing as by the sweat, the space around the hair is large and the accumulated secretion of the hair glands and the desquamated cells furnish a material in which bacteria may grow. Growing as a mass in this situation, they may produce sufficient toxic material to destroy adjacent living cells and thus effect entrance. Infection from the eye is not common, the surface, though moist, is smooth; the eyelashes around the margin of the lids give some mechanical protection from the entrance of bacteria contained in dust, and the movements of the lids and the constant and easily accelerated secretion of tears act mechanically in removing foreign substances. It is possible that the mechanical cleansing of the skin by the daily bath may have some action in preventing infection.
The internal surfaces are much more exposed to attack and the protection is not so efficient. The moisture of these surfaces is both a protection and a source of danger. It protects by favoring the lodgment near the orifices of organisms which are in the inspired air, for when bacteria touch a moist surface they cannot be raised from this and carried further by air currents. The moisture is a source of danger in that it favors the growth of bacteria which lodge on the surface. The respiratory surface which is most exposed to infection from the air is further protected by the cilia, which are fine hair-like processes covering the cells of the surface and which by their constant motion sweep out fine particles of all sorts which lodge upon them. The cavity of the mouth harbors large numbers of organisms, many of them pathogenic. It forms a depot from which bacteria may pass to communicating surfaces and infection from these may result. Food particles collect in the mouth and provide culture material, and there are many crypts and irregularities of surface which oppose mechanical cleaning. Infection of the middle ear, the most common cause of deafness, takes place by means of the Eustachian tube which connects the cavity of the ear with the mouth. Organisms from the mouth can extend into the various large salivary glands by means of the ducts and give rise to infections. The tonsils, particularly in children, provide a favorable surface for infection. The mucous surface extends into these forming deep pockets lined with very thin epithelium, and in these débris of all sorts accumulates and provides material favorable for bacterial growth.
The lungs at first sight seem to offer the most favorable surface for infection. The surface, ninety-seven square yards, is enormous; it is moist, the epithelial covering is so thin as to give practically no mechanical protection, large amounts of air constantly pass in and out, and the surface is in contact with this. They are protected from infection in many ways. The tubes or bronchi by which the air passes into and from the lungs are covered with cilia; the surface area of these tubes constantly enlarges as they branch, the sum of the diameters of the small tubes being many times greater than that of the windpipe, and this enlargement by retarding the motion of the air favors the lodgment of particles on the surface whence they are removed by the action of the cilia. The entering air is also brought closely in contact with a moist surface at the narrow opening of the larynx. That bacteria and other foreign substances can enter the lungs in spite of these guards is shown not only by the infections which take place here, but also by the large amount of black carbon deposited in them from the soot contained in the air.
Infection rarely takes place from the surface of the gullet or oesophagus which leads from the mouth to the stomach. This is due to the smoothness of the surface and to the rapidity with which food passes over it. Infection by the stomach also is rare, for this contains a strong acid secretion which destroys many of the bacteria which are taken in with the food. It is found impossible to infect animals with cholera unless the acidity of the stomach contents be neutralized by an alkali. Many organisms, although their growth in the stomach is inhibited, are not destroyed there and pass into the intestines, where the conditions for infection are more favorable. This large and very irregular surface is bathed in fluid which is a good culture medium and but a single layer of cells covers it. The organisms which cause many of the infectious diseases in both man and animals find entrance by means of the alimentary canal, as cholera, dysentery, typhoid fever, chicken cholera, hog cholera.
Infection by the genito-urinary surface is comparatively rare. The surface openings are usually closed, and the discharge of urine has a mechanical cleansing effect. The wide tube of the vagina is further protected by a normal bacterial flora which produces conditions hostile to other and pathogenic bacteria. The most common infections are the sexual diseases, which are due to organisms which find favorable conditions for growth in and on the surface and which are conveyed from a similar surface by sexual contact.
It remains a question whether bacteria can penetrate an intact surface producing no injury at the point of entrance and be carried by the lymph or blood into internal organs where they produce disease. Internal infections are often found with seemingly intact body surfaces, but it is impossible to exclude the presence of minute or microscopic surface injuries by which the organisms may have entered. It is also possible that a slight injury at the point of entrance may heal so completely as to leave no trace.
The chief danger from wounds is that their surfaces may become infected. Death from wounds is due more frequently to infection than to the actual injury represented by the wounds. Much depends upon the character of the wound. Infection of clean wounds which are made by a sharp cutting instrument and from which there is abundant hæmorrhage with sealing of the edges of the wound by clotted blood, rarely happens. Typical wounds of this sort are often made in shaving, and infection of such wounds is extraordinarily rare. If, with the wound, pathogenic organisms are placed in the tissue, or foreign substances such as bits of clothing are carried in with a bullet, for example, or if the instrument causing the wound be of such a character as to produce extensive lacerations of tissue, infection is more apt to occur. The less frequency of infection in modern wars is in part due to the simpler character of the wounds and in part to the fact that modern fixed ammunition is practically free from germs. The old spear-head, the arrow, the cross bow bolt, had little regard for the probabilities of infection. Whether infection follows a wound depends both upon the entry of pathogenic organisms and upon these finding in the tissues suitable opportunities for growth. In wounds in which there is much laceration of tissue organisms find the most favorable conditions for development. The very slight wounds produced by the exploded cap in the toy pistol give suitable conditions for the development of the bacillus which produces tetanus or lockjaw. The deaths of children from lockjaw following a Fourth of July celebration have often exceeded the total deaths in a Central American revolution. The tetanus bacillus is a widely distributed organism, whose normal habitat is in the soil and which is usually present on the dirty hands of little boys. The toy-pistol wounds are made by small bits of paper or metal being driven into the skin by the explosion of the cap. The wound is of little moment, the surface becomes closed, and a bit of foreign substance, a few dead cells and the tetanus bacilli from the surface remain enclosed and in a few days the fatal disease develops. Infection of the surfaces of old wounds such as the surface of an ulcer takes place with difficulty. Large numbers of leucocytes which give protection by phagocytosis are constantly passing to the surface, and there is also a constant stream of fluid towards the surface. On such a surface there may be an abundant growth of pathogenic organisms, but no infection results.
In most infections there is a focus where the infectious organisms are localized; this may correspond to the point of entrance on a surface or it may be in the interior of the body, the organisms being deposited there after entrance. At this primary localization, the atrium of infection,[9] the organisms multiply and from this point further invasion takes place. Many secondary foci may be formed in the organs by distribution of the organisms, or there may be infection of the blood and fluids of the body. The injuries which are produced depend upon the nature of the infecting organisms. The most common lesion consists in the death of the tissue about the infecting organisms. In most cases the sum of the changes are so characteristic that from them the nature of the infection is easily determined, and these changes often give names to the disease; thus tuberculosis is a disease characterized by the formation of tubercles or little nodules in the body. The situation of the foci of disease is determined by many conditions, the most important being the varying resistance of the different organs of the body to the growth of bacteria. Certain organs, such as the central nervous system, the muscles, the testicles and the ovaries, have a high resistance to the growth of bacteria. The disease may be localized in certain organs because only in these do the bacteria find favorable conditions for growth. In spite of a high general resistance to infection the lesions in chronic glanders are most marked in the muscles, those of poliomyelitis in the spinal cord. There are few bacterial diseases which are localized in the blood, but many of the diseases caused by protozoa have this localization. In every infection some organisms enter the blood, which acts as a carrier and deposits them in the organs.
Bacteria cause disease by producing substances called toxines which are poisonous to the cells, and of which two sorts are distinguished. One form of toxines is produced by the bacteria as a sort of secretion, and is formed both in the body and when the bacteria are growing in cultures. Substances of this character, many of them highly poisonous, are produced both by animals and plants. They may serve the purpose both of offence and defence, as in the case of the snake venom, and in other cases they seem to benefit their producers in no way whatever, and may even be injurious to them. After the different cereals have been grown for succeeding years in the same place, growth finally diminishes not from the exhaustion of the soil, but from the accumulation in it of substances produced by the plants. Beneath certain trees, as the Norway maple, grass will not grow, and it has been shown that the tree produces substances which inhibit the growth of grass. When bacteria are grown in a culture flask, growth ceases long before the nutritive material has been consumed, from the accumulation of waste products in the fluid. The other class of toxic substances, called endotoxines, are not secretion products, but are contained in the bacterial substance and become active by the destruction and disintegration of the bacteria. They can be artificially produced by grinding up masses of bacteria, and in the body the destruction and solution of bacteria which is constantly taking place sets them free. The toxines and the endotoxines are of an albuminous nature, and act only when they come in contact with the living cells within the body. When taken into the alimentary canal they are either not absorbed or so changed by the digestive fluids as to be innocuous. Many of the ordinary food substances, even a material apparently so simple as the white of an egg, are highly injurious if they reach the tissues in an unchanged form.
By means of these substances the bacteria produce such changes in their environment within the body that this becomes adapted to their parasitic existence. In symbiosis the bacteria probably undergo changes by which they become adapted to the environment, and in parasitism the environment becomes adapted to them. In the same way man can change his immediate environment by means of clothing, artificial heating, etc., and adapt it to his needs; or by hardening his body he can adapt it to the environment. The pathogenic bacterium finds the living tissue hostile, its cells devour him, the tissue fluids destroy him, and by means of the toxines he changes the environment from that of living to dead tissue, or in other ways so alters it that it is no longer hostile. The parasite has also means of passive defence comparable to the armor of the warrior in the past. It may form a protective mantle called a capsule around itself, which serves to protect it from the action of the body fluids. Such capsule formation is a very common thing in the pathogenic organisms, and they are found only when these are growing in the body and do not appear in cultures (Fig. 17-c).
It is evident that just as the parasite has his weapons of offence and defence so has the host, otherwise there would be no recovery from infectious diseases. Although many of the infectious diseases have a high mortality, which in rare instances reaches one hundred per cent, the majority do recover. In certain cases the recovery is attended by immunity, the individual being protected to a greater or less degree from a recurrence of the same disease. The immunity is never absolute; it may last for a number of years only, and usually, if the disease be again acquired, the second attack is milder than the primary. Probably the most enduring immunity is in smallpox, although cases are known of two and even three attacks; the immunity is high in scarlet fever, measles, mumps and typhoid fever. The immunity from diphtheria is short, and in pneumonia, although there must be a temporary immunity, future susceptibility to the disease is probably increased. In certain cases the immunity is only local; the focus of disease heals because the tissue there has evolved means of protection from the parasite, but if any other part of the body be infected, the disease pursues the usual course. A boil, for example, is frequently followed by the appearance of similar boils in the vicinity due to the infection of the skin by the micrococci from the first boil, which by dressings, etc., have become spread over the surface.
The natural methods of defence of the host against the parasites have formed the main subject in the study of the infectious diseases for the last twenty years. Speculation in this territory has been rife and most of it fruitless, but by patient study of disease in man and by animal experimentation there has been gradually evolved a sum of knowledge which has been applied in many cases to the treatment of infectious diseases with immense benefit. Research was naturally turned to this subject, for it was evident that the processes by which the protection of the body was brought about must be known before there could be a really rational method of treatment directed towards the artificial induction of such processes, or hastening and strengthening those which were taking place. Previous to knowledge of the bacteria, their mode of life, their methods of infection and knowledge of the defences of the body, most of the methods of prevention and treatment of the infectious diseases was based largely on conjecture, the one brilliant exception being the discovery of vaccination by Jenner in 1798.
The host possesses the passive defences of the surfaces which have already been considered. The first theories advanced in explanation of immunity were influenced by what was known of fermentation. One, the exhaustion theory, assumed that in the course of disease substances contained in the body and necessary for the growth of the bacteria became exhausted and the bacteria died in consequence. Another, the theory of addition, assumed that in the course of the disease substances inimical to the bacteria were formed. Both these theories were inadequate and not in accord with what was known of the physiology of the body. The most general mode of defence is by phagocytosis, the property which many cells have of devouring and digesting solid substances (Fig. 16-p). Although this had been known to take place in the amoebæ and other unicellular organisms, the wide extent of the process and its importance in immunity was first recognized by Metschnikoff in 1884 and the phagocytic theory of immunity advanced and defended by a brilliant series of experiments by Metschnikoff and his pupils conducted in the Pasteur Institute. Metschnikoff's first observations were made on the daphnea, a small animalcule just visible to the naked eye which lives in fresh water. The structure of the organism is simple, consisting of an external and internal surface between which there is a space, the body cavity; daphneæ are transparent and can be studied under the microscope while living. Metschnikoff observed that certain of them in the aquarium gradually lost their transparency and died, and examining these he found they were attacked by a species of fungus having long, thin spores. These spores were taken into the intestine with other food; they penetrated the thin wall of the intestine, passed into the body cavity, multiplied there, and in consequence the animal died. In many cases, however, those penetrating became enclosed in cells which the body cavity contains and which correspond with the leucocytes of the blood; in these the spores were digested and destroyed. The daphneæ in which this took place recovered from the infection. Here was a case in which all the stages of an infectious disease could be directly followed under the microscope, and the whole process was simple in comparison with infections in the higher animals. The pathogenic organism was known, the manner and site of invasion was clear, it was also evident that if the multiplication of the parasite was unchecked the animal died, but if the parasite was opposed by the body cells and destroyed the animal recovered. The studies were carried further into the diseases of the higher animals, and it was found the leucocytes in these played the same part as did the cells in the body cavity of the daphnea. The introduction of bacteria into certain animals was followed by their destruction within cells and no disease resulted; if this did not take place, the bacteria multiplied and produced disease. Support also was given the theory by the demonstration at about the same time that in most of the infectious diseases the leucocytes of the blood became increased in number,—that in pneumonia, for instance, instead of the usual number of eight thousand in a cubic millimeter of blood, there were often thirty thousand or even fifty thousand. At about the same time also chemotaxis, or the action of chemical substances in attracting or repelling organisms, excited attention, and all these facts together became woven into the theory. It was soon seen, however, that this theory, based as it was on observation and supported by the facts observed, was not, at least in its first crude form, capable of general application. Many animals have natural immunity to certain diseases; they do not have the disease under natural conditions, nor do they acquire the disease when the organisms causing it are artificially introduced into their tissues by inoculation. Such natural immunity seemed to be unconnected with defence by phagocytosis, for the leucocytes of the animal might or might not have phagocytic reaction to the particular organisms to which the animal was immune. It was also seen that recovery from infection in certain diseases was unconnected with phagocytosis. It had also been demonstrated, by German observers chiefly, that the serum of the blood, the colorless fluid in which the corpuscles float, was itself destructive, and that in an animal rendered immune to a special bacterium the destructive action of the serum on that organism was greatly increased. In this hostile serum the bacteria often became clumped together in masses, the bodies became swollen, broken up, and finally disintegrated. This property of the serum was described as due to a substance in the serum called alexine, which in the immune animal became greatly increased in amount. It was even denied by some that phagocytosis of living bacteria took place, and that all those included in the cells were dead, having been destroyed in the first instance by the serum. The strife became a national one between the French and Germans,—on the one side in France the phagocytic theory was defended, and in Germany, on the other, the theory of serum immunity. The mass of experimental work which poured from the laboratories of the two countries in attack and defence became so great that it could not easily be followed. It had a good influence because, without the stimulation of this national rivalry, the knowledge which gradually arose from this work would not have been so quickly acquired. It is interesting that the mode of action of the serum in destroying bacteria was demonstrated not by a German but by Bordet, a French observer and a pupil of Metschnikoff. He showed that the serum contained two distinct substances, each necessary for the destructive action. The separate action of these substances can be studied since one is thermolabile, or destroyed by heating the serum to one hundred and thirty-three degrees; the other thermostabile, or capable of withstanding a greater degree of heat. These substances are known only by their effect, they have never been separated from the serum. The thermostabile substance, or amboceptor, as it is generally called, has in itself no destructive action on the bacteria; but in some way so alters them that they can be acted on by the thermolabile substance called complement whose action is destructive. The amount of amboceptor may increase in the course of infection and its formation stimulated, the amount of complement remains unchanged. The action of the amboceptor is specific, that is, directed against a single species of bacterium only; the destructive power of the blood may be very great against a single bacterium species and have no effect on others. There seem naturally to be many different amboceptors in the blood, and the number may be very greatly increased. It has been shown as a result of the work of many investigators that the shield has two faces,—there is destruction both by cells and fluids and there is interaction by both. The amboceptors so necessary for the destructive action of the serum are produced by the body cells, particularly the leucocytes. The serum assists in pagocytosis by the action on bacteria of substances called opsonins which are contained in it, and the formation of which can be very greatly stimulated. Again, not all inclusion of bacteria within leucocytes is indicative of phagocytosis; in many cases the bacteria seem to find the best conditions for existence within the leucocytes, and these and not the bacteria are destroyed.
So far it has been shown that the best defence of the body is, as is the best defence in war, by offensive measures, as illustrated by phagocytosis and destruction by the serum. Both of these actions can be increased by their exercise just as the strength of muscular contraction can be increased by exercise, and the facility for doing everything increased by habit. Certain of the infectious diseases are, as has been said, essentially toxic in their nature, and in cultures the organisms produce poisonous substances. By the injection into the tissues of such substances the same disturbances are produced as when the bacteria are injected. Such a disease is diphtheria. In this there is only a superficial invasion of the tissues. The diphtheria bacilli are located on the surface of the tonsils or pharynx or windpipe, where, as a result of their action, the membrane so characteristic of the disease is produced. The membrane may be the cause of death when it is so extensively formed as to occlude the air passages, but the prominent symptoms of the disease, the fever, the weakness of the heart and the great prostration are due not to the presence of the membrane, but to the action of toxic substances which are formed by the bacteria growing in the superficial lesions and absorbed. Tetanus, or lockjaw, is another example of these essentially toxic diseases. The body must find some means of counteracting or destroying these injurious toxic substances. It does this by forming antagonistic substances called antitoxines, which act not by destroying the toxines, but by uniting with them, the compound substance being harmless. It has been found that the production of antitoxine can be so stimulated by the injection of toxine that the blood of the animal used for the purpose contains large amounts of antitoxine. The horse is used in this way to manufacture antitoxine, and the serum injected into a patient with diphtheria has a curative action, a greater amount being thus introduced than the patient can manufacture.
Fig. 18—Diagram To Illustrate Ehrlich'S Theory Of Antitoxine Formation. The surface of the cell (n) is covered with receptors some of which (b) fit the toxine molecule, (a) allowing the toxine to act upon the cell. Under the stimulus of this the cell produces these receptors in excess which enter into the blood and there combine with the toxine as in a^1 b^1, thus anchoring it and preventing it from acting upon the cells. The receptors c and d do not fit the toxine molecule.
A very ingenious theory which well accords with the facts has been given by Ehrlich in explanation of the production of antitoxine and of the reaction between toxine and antitoxine (Fig. 18). This is based on the hypothesis, which is in accord with all facts and generally accepted, that the molecules which enter into the structure of any chemical substance have in each particular substance a definite arrangement, and that in a compound substance each elementary substance entering into the compound molecule has chemical affinities, most of which may be satisfied by finding a suitable mate. Ehrlich assumes that the very complex chemical substances which form the living cells have many unsatisfied chemical affinities, and that it is due to this that molecules of substances adapted for food can enter the cells and unite with them; but there must be some coincidence of molecular structure to enable the union to take place, the comparison being made of the fitting of a key into a lock. The toxines—that produced by the diphtheria bacillus being the best example—are substances whose molecular structure enables them to combine with the cells of the body, the combination being effected through certain chemical affinities belonging to the cells termed receptors. Unless the living cells have receptors which will enable the combination with the toxine to take place, no effect can be produced by the toxine and the cells are not injured. This is the case in an animal naturally immune to the action of the diphtheria bacillus or its toxines. In the case of the susceptible animal the receptors of the cells of the different organs combine with the toxine to a greater or less extent, which explains the fact that different degrees of injury are produced in the different tissues; the toxine of tetanus, or lockjaw, for example, combines by preference with the nervous tissue, that of diphtheria with the lymphatic tissue. It is known that in accordance with the general law of injury and repair, a loss in any part of the body stimulates the tissue of the same kind to new growth and the loss is thus repaired; it is assumed that the cell receptors which combine with the toxine are lost for the cell which then produces them in excess. The receptors so produced pass into the blood, where they combine with the toxine which has been absorbed; the combination is a stable one, and the toxine is thus prevented from combining with the tissue cells. The antitoxine which is formed during the disease, and the production of which in the horse can be enormously stimulated by the injection of toxine, represents merely the excess of cell receptors, and when the serum of the horse containing them is injected in a case of diphtheria the same combination takes place as in the case of receptors provided by the patient. In the case of the destruction of bacteria in the blood by the action of amboceptor and complement, the amboceptor must be able to combine with both the bacterial cell and the complement which brings about its destruction, and just as antitoxine is formed so new amboceptors may be formed.
Few hypotheses have been advanced in science which are more ingenious, in better accord with the facts, have had greater importance in enabling the student to grasp the intricacies of an obscure problem, and which have had an equal influence in stimulating research. The immunity which results from disease in accordance with this theory, is due not to conditions preventing the entrance of organisms into the body, but to greater aptitude on the part of the cells to produce these protective substances having once learned to do so. An individual need not practise for many years, having once learned them, those combinations of muscular action used in swimming; but the habit at once returns when he falls into the water.
Infectious diseases and recovery are phases of the struggle for existence between parasite and host, and illustrate the power of adaptation to environment which is so striking a characteristic of living matter.